Inhibitors of human immunodeficiency virus (HIV) protease have been approved for use in the treatment of HIV infection for several years. A particularly effective HIV protease inhibitor is (2S,3S,5S)-2-(2,6-dimethylphenoxyacetyl)amino-3-hydroxy-5-(2-1-tetrahydropyrimid-2-onyl)-3-methylbutanoyl)amino-1,6-diphenylhexane, also known as Lopinavir. Lopinavir is represented by the following structure.

Lopinavir is known to have ability of inhibiting HIV protease and the HIV infection. Lopinavir is particular effective for the inhibition of HIV protease and for the inhibition of HIV infection when co administered with Ritonavir.
Lopinavir may be prepared using the procedures described in U.S. Pat. No. 5,914,332. This patent also disclosed a process for the preparation of amorphous lopinavir.
Pharmaceutical compositions comprising lopinavir or a pharmaceutically acceptable salt thereof were disclosed in U.S. Pat. No. 5,914,332.
Polymorphism is defined as “the ability of a substance to exist as two or more crystalline phases that have different arrangement and/or conformations of the molecules in the crystal Lattice. Thus, in the strict sense, polymorphs are different crystalline forms of the same pure substance in which the molecules have different arrangements and/or different configurations of the molecules”. Different polymorphs may differ in their physical properties such as melting point, solubility, X-ray diffraction patterns, etc. Although those differences disappear once the compound is dissolved, they can appreciably influence pharmaceutically relevant properties of the solid form, such as handling properties, dissolution rate and stability. Such properties can significantly influence the processing, shelf life, and commercial acceptance of a polymorph. It is therefore important to investigate all solid forms of a drug, including all polymorphic forms, and to determine the stability, dissolution and flow properties of each polymorphic form. Polymorphic forms of a compound can be distinguished in the laboratory by analytical methods such as X-ray diffraction (XRD), Differential Scanning Calorimetry (DSC) and Infrared spectrometry (IR).
Solvent medium and mode of crystallization play very important role in obtaining a crystalline form over the other.
Lopinavir can exist in different polymorphic forms, which differ from each other in terms of stability, physical properties, spectral data and methods of preparation.
WO Patent Publication No. 2001/74787 (herein after referred to as the '787 patent publication) described various polymorphic forms of lopinavir and processes for their preparation. The Publication described the formation of several polymorphic forms of lopinavir, which were designated lopinavir crystal form of Type I hydrated, Type I higher hydrated, Type II isopropanol hemisolvate, Type II isopropanol solvate, Type II ethyl acetate hemisolvate, Type II ethyl acetate solvate, Type II chloroform hemisolvate, Type III ethyl acetate solvated, Type III desolvated and Type IV non-solvated.
According to the '787 patent publication, Type I hydrated crystal form of lopinavir (characterized by an X-ray powder diffraction pattern having peaks expressed as 2θ at about 7.25, 8.53, 10.46, 11.05, 11.71, 14.76, 15.30, 16.67, 17.32, 19.10, 19.57, 21.24, 21.84 and 22.46±0.1 degrees) can be prepared by crystallization of lopinavir from solution or suspension in water or from solutions in mixtures of water and water miscible organic solvents such as methanol, ethanol and acetonitrile.
According to the '787 patent publication, Type I higher hydrated crystal form of lopinavir (characterized by an X-ray powder diffraction pattern having peaks expressed as 2θ at about 3.89, 6.55, 7.76, 8.55, 9.70, 10.56, 14.76, 15.57, 18.30, 18.95 and 22.74±0.1 degrees) can be prepared by crystallization of hydrated lopinavir from a warm solution in a mixture of water and ethanol, followed by extended exposure to an elevated relative humidity environment.
According to the '787 patent publication, Type III ethyl acetate solvated crystal form of lopinavir (characterized by an X-ray powder diffraction pattern having peaks expressed as 2θ at about 4.85, 6.52, 7.32, 12.82, 12.96, 16.49 and 19.31±0.1 degrees) can be prepared by slow addition of an heptane to a heated solution of lopinavir in the ethyl acetate, thereby inducing crystallization and then isolation by filtration.
According to the '787 patent publication, Type III desolvated crystal form of lopinavir (characterized by an X-ray powder diffraction pattern having peaks expressed as 2θ at about 4.85, 6.39, 7.32, 8.81, 12.20, 12.81, 14.77, 16.45 and 17.70±0.1 degrees, and the DSC thermogram having a melting endotherm with onset at 95 deg C. and peak at 98 deg C.) can be prepared by crystallization from acetonitrile.
According to the '787 patent publication, Type IV non-solvated crystal form of lopinavir (characterized by an X-ray powder diffraction pattern having peaks expressed as 2θ at about 6.85, 9.14, 12.88, 15.09, 17.74, 18.01 and 18.53±0.1 degrees, and the DSC thermogram having a melting endotherm with onset at 117 deg C. and peak at 122 deg C.) can be prepared from acetonitrile by slow cooling and slow evaporation of a saturated solution or by exposure of amorphous lopinavir to an acetonitrile atmosphere.
WO Patent Publication No. 2009/004653 disclosed a process for preparing an amorphous form of lopinavir.
We have discovered a stable novel desolvated crystalline form of lopinavir and cyclohexane solvate of lopinavir.
One object of the present invention is to provide a novel cyclohexane solvate form of lopinavir and a process for preparing it.
According to another object of the present invention is to provide a novel desolvated crystalline form of lopinavir and a process for preparing it.
Still another object of the present invention is to provide pharmaceutical composition of a novel desolvated crystalline form of lopinavir.